Method for producing biperiden IV

ABSTRACT

The invention relates to a method for producing biperiden by reacting exo-1-(bi-cyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with a phenylmagnesium compound. According to the invention, exo-1-(bi-cyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone can be obtained by reacting the exo-ether of enol silylene of formula (IV) with a compound of N-methylenepiperidinium.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Section 371 National Stage Application ofapplication No. PCT/EP02/05497 filed on May 17, 2002.

The present invention relates to a method for producing biperiden.

Biperiden is a well-known central anticholinergic agent and is employedfor the treatment of Parkinson's disease (Ullmanns Enzyklopädie dertechnischen Chemie, 4the edition, volume 21, Verlag Chemie, 1982, p.627). It comprises a racemate of1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,R))-1-phenyl-3-piperidino-propanol(1,S)and1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,S))-1-phenyl-3-piperidinopropanol(1,R)(Ia) and represents one of four possible pairs of enantiomers (Ia-d) ofthe amino alcohol1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I).

DE 1 005 067 and U.S. Pat. No. 2,789,110 describe the preparation of theamino alcohol I by reacting1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with aphenylmagnesium halide. U.S. Pat. No. 2,789,110 additionally describesthe preparation of the propanone II starting from1-(bicyclo[2.2.1]hept-5-en-2-yl)-ethanone (III), paraformaldehyde andpiperidine hydrochloride in a Mannich reaction, and the preparation ofthe ethanone III from cyclopentadiene and methyl vinyl ketone in aDiels-Alder cycloaddition.

Neither DE 1 005 067 nor U.S. Pat. No. 2,789,110 disclose whether theamino alcohol I obtained in this way is a mixture of isomers or a pureisomer.

The precursor for preparing the propanol,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), canexist in two isomeric forms, as exo or as endo isomer (II-exo, II-endo),and only the exo form is able to afford biperiden in the abovementionedreaction with a phenylmagnesium halide.

The structural formulae of II-exo and of II-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation II-exo orII-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III), the starting substancefor synthesizing the propanone II, may also exist both as exo and asendo isomer (III-exo, III-endo) and, correspondingly, only reaction ofthe exo isomer leads in the subsequent steps to biperiden.

The structural formulae of III-exo and of III-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation III-exoor III-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

It is not possible to infer any information about the configuration ofthe precursors III and intermediates II employed in any of theabovementioned publications.

It is known that 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) isobtained from the cycloaddition in an exo/endo ratio of 1:4 (e.g. R.Breslow, U. Maitra, Tetrahedron Letters, 1984, 25, 1239). Since theprior art mentioned at the outset makes no statements at all about thestereochemistry of the ethanone III, it must be assumed that theethanone III was employed in this ratio of isomers to prepare the aminoalcohol I.

The preparation of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone(III-exo) was described in 1965 by J. G. Dinwiddie and S. P. McManus (J.Org. Chem., 1965, 30, 766). This entails exo/endo mixtures of1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) in which the endo contentpredominates being heated in methanol in the presence of sodiummethanolate and isomerizing to mixtures with an exo content of about70%. It is possible to obtain from this by fractional distillation and,where appropriate, redistillation of the distillateexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a purity ofup to 95%.

Experiments by the applicant has shown that even on use of pure exoethanone III-exo as starting material in the Mannich reaction there isalways production of an exo/endo mixture of the propanone II. Thisdisadvantage is in relation to the yield of pure biperiden (Ia) in thesubsequent reaction of the propanone II to give the propanol I. Purebiperiden means the biperiden (Ia) with a purity of at least 99.0%, asis generally necessary for pharmaceutical applications.

It is an object of the present invention to provide a method forproducing biperiden which provides the latter in a higher yield, thismethod including a method for producing exo propanone II-exo of maximumisomeric purity. Exo propanone II-exo is intended to mean a propanone IIwhich is at least 96%, preferably at least 97%, and particularlypreferably at least 98% composed of the exo isomer II-exo. Biperiden isintended to mean a substance of the structural formula Ia.

It has been possible to achieve the object by a method for producingbiperiden (Ia) by reactingexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II-exo)with a phenyl-magnesium compound, characterized in that the productionof the exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone(II-exo) comprises the following steps:

-   -   a) conversion of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone        (III-exo) into an exo silyl enol ether IV

-   -   -   in which R may be identical or different and is an alkyl            group or a cycloalkyl group, and

    -   b) reaction of the exo silyl enol ether IV with an        N-methylenepiperidinium compound.

The structural formula of the exo silyl enol ether IV shows for the sakeof simplicity only one of two possible enantiomers. However, the termexo silyl enol ether IV refers hereinafter to the pair of enantiomers.

Exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) is intendedhereafter to mean an ethanone III which is at least 96%, preferably atleast 97% and particularly preferably at least 98% composed of the exoisomer III-exo. A corresponding statement applies to the exo silyl enolether IV.

The exo isomers employed in the method of the invention are, as alreadydescribed for the exo ethanone III-exo, the exo propanone II-exo and forthe exo silyl enol ether IV, pairs of enantiomers. In order to obtainbiperiden (Ia), which is itself a racemate, racemic mixtures ofenantiomers of the starting materials and of the intermediates areemployed. However, the method of the invention can also be applied topure enantiomers and to nonracemic mixtures of enantiomers.

The exo ethanone III-exo is converted into the corresponding exo silylenol ether IV in general by first converting the exo ethanone III-exowith a base into the exo enolate V and then reacting the latter with asuitable silyl compound.

The structural formula of the exo enolate V shows for the sake ofsimplicity only one or two possible enantiomers. However, the term exoenolate V refers hereinafter to the pair of enantiomers.

Exo enolate V is intended to mean hereinafter an enolate V which is atleast 96%, preferably at least 97% and particularly preferably at least98% composed of the exo isomer.

Suitable silyl compounds for reaction with the exo enolate V arecompounds of the general formula R₃Si-X in which R has theaforementioned meanings, and X is a nucleophilically displaceableleaving group, preferably a halogen atom and in particular chlorine. Inthis connection, alkyl preferably has 1 to 4 carbon atoms, i.e. isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl or tert-butyl. In this connection, cycloalkyl preferably has 5to 8 carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl. Particularly preferred silyl compounds ale thetri-C₁-C₄-alkylsilyl halides, and tri-C₁-C₄-alkylsilyl chlorides areparticularly used. Trimethylsilyl chloride is particularly preferablyemployed.

The exo ethanone III-exo and the silyl compound are ordinarily employedin a molar ratio in the range from 1:1 to 1:2. The silyl compound ispreferably employed in excess, preferably in an excess of from 10 to 100mol %, in particular from 10 to 30 mol %, e.g. of 20 mol %.

The reaction generally takes place at a temperature in the range from−100 to 0° C., preferably from −85 to −10° C. and particularlypreferably from −80 to −60° C., e.g. at −78° C.

The bases ordinarily used for the treatment of the exo ethanone III-exowith a base to convert into the exo enolate V are metal amides. Alkalimetal amides are preferably used, in particular lithium amides. Theamide nitrogen is preferably substituted once or twice. Suitablesubstituents on the amide nitrogen are C₁-C₄-alkyl radicals such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl,also C₅-C₈-cycloalkyl radicals such as cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl which may in turn have 1 to 4 methyl groups,and tri-C₁-C₄-alkylsilyl radicals such as trimethylsilyl ortriisopropylsilyl. The amide nitrogen may additionally be disubstitutedin such a way that it forms part of a saturated 5- or 6-memberedheterocycle which may in turn be substituted by 1, 2, 3 or 4 C₁-C₄-alkylgroups, especially methyl groups, such as, for example, in the amides ofpiperidine, 2,2,6,6-tetramethyl-piperidine or pyrrolidine. The amidenitrogen is preferably disubstituted. Lithium diisopropylamide isparticularly preferably employed as base.

Reaction of the exo ethanone III-exo with the base generally takes placein a suitable solvent in a molar ratio of the exo ethanone III-exo tothe base in the range of 1:1 to 1:1.5, preferably from 1:1 to 1:1.2 andparticularly preferably virtually equimolar.

Reaction of the exo ethanone III-exo with the base is ordinarily carriedout in an inert solvent. Solvents suitable for this purpose are C₅-C₉aliphatic compounds such as n-hexane or n-heptane, aromatic compoundssuch as benzene, toluene, xylenes or ethylbenzene, aliphatic C₄-C₈ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl etheror 1,2-dimethoxyethane, alicyclic C₄-C₆ ethers such as tetrahydrofuranor dioxane or mixtures thereof. The solvents are ordinarily employedanhydrous, as usual for such reactions. In a specific embodiment of themethod of the invention, a mixture of tetrahydrofuran, ethylbenzene andn-heptane is employed as solvent when lithium diisopropylamide is usedas base.

Reaction of the exo ethanone III-exo with the base ordinarily takesplace at a temperature in the range from −100° C. to 0° C., preferablyfrom −85 to −10° C. and particularly preferably from −80 to −60° C.,e.g. at −78° C. It is possible for the reaction to add the base to theexo ethanone III-exo or, conversely, to add the exo ethanone III-exo tothe base, and the latter possibility is preferred. It is suitable forthis purpose to add the exo ethanone III-exo to the solution of the basein one or more of the abovementioned solvents at the temperaturesdescribed above. The concentration of the base in the solution isnormally from 0.1 to 10 mol/l, preferably 1 to 3 mol/l. The exo ethanoneIII-exo is generally added in portions; the exo ethanone III-exo ismoreover added undiluted or dissolved in one or more of theabovementioned solvents, preferably in the same solvent(s) in which thebase is dissolved, in a concentration of from 0.1 to 20 mol/l,preferably from 1 to 15 mol/l. However, the exo ethanone III-exo ispreferably added in pure form. To complete the reaction, the mixture canbe left in the temperature range defined above for from 10 minutes to,for example, 5 hours, preferably 30 minutes to one hour, during which itis preferably stirred.

To the reaction mixture which has been obtained in this way and whichcontains the exo enolate V, one of the organosilicon compounds describedabove is added, normally in situ, i.e. without previous isolation of theenolate, in the temperature range defined above. The silyl compound canbe added all at once or, preferably, over a period of from 5 minutes upto several hours, in particular from 10 minutes up to one hour,undiluted or dissolved in one or more of the abovementioned solvents.The silyl compound is preferably added in pure form. On addition ofsolution, the concentration of the silyl compound is ordinarily from 0.1to 20 mol/l, preferably 1 to 15 mol/l. To complete the reaction, thereaction mixture is ordinarily left for some time, e.g. from 1 to 5hours, during which it is preferably stirred. It is moreover possiblefor the temperature of the mixture to be left at the abovementionedvalues or, preferably, allowed to reach room temperature, e.g. byremoving the cooling apparatus

Both the production of the exo enolate V and reaction thereof to givethe exo silyl enol ether IV suitably take place under an inert gasatmosphere. Examples of suitable inert gases are nitrogen and the noblegases such as argon.

The reaction mixture is preferably worked up by aqueous extraction. Thecrude exo silyl enol ether IV obtained therefrom is purified whereappropriate by distillation, preferably in vacuo. The exo silyl enolether IV obtained in this way is novel and, is a valuable intermediatefor producing biperiden (Ia), the present invention likewise relatesthereto.

The subsequent reaction of the exo silyl enol ether IV with anN-methylenepiperidinium compound to give the exo propanone II-exogenerally takes place in a suitable polar aprotic organic solvent.Suitable polar aprotic organic solvents include aliphatic C₄-C₈ etherssuch as diethyl ether, diisopropyl ether or 1,2-dimethoxyethane,alicyclic C₄-C₆ ethers such as tetrahydro-furan or dioxane, chlorinatedC₁-C₂ aliphatic compounds such as dichloromethane, carboxylic acidderivatives such as acetonitrile, N,N-dimethylformamide orN-alkylpyrrolidones, e.g. N-methyl-2-pyrrolidone, and sulfoxides such asdimethyl sulfoxide. N,N-Dimethylformamide or N-methyl-2-pyrrolidone ispreferably used. The solvents are ordinarily employed anhydrous, asusual for reactions with N-methylenepiperidinium compounds.

The exo silyl enol ether IV and the N-methylenepiperidinium compound arepreferably employed with a molar ratio of IV to N-methylenepiperidiniumcompound in the range from 1:1 to 1:2. The N-methylenepiperidiniumcompound is employed in particular in excess, e.g. in an excess of from10 to 100 mol %, particulary preferably 20 to 70 mol %, e.g. 50 mol %,based on IV.

The exo silyl enol ether IV is preferably introduced into the solvent ata temperature in the range from −60 to 10° C., in particular from −40 to0° C. and particularly preferably from −30 to −15° C. and then, at thesetemperatures, the N-methylenepiperidinium compound is added. Theaddition can take place in one portion or over a period of from 5minutes up to several hours. To complete the reaction, the mixture issuitably left for some time, e.g. 15 minutes to 5 hours, during which itis preferably stirred. It is moreover possible to leave the mixture inthe temperature range defined above or preferably allow it to reach roomtemperature.

It is, of course, also possible to add the exo silyl enol ether IV tothe N-methylenepiperidinium compound, but addition of theN-methylenepiperidinium compound to the exo silyl enol ether IV ispreferred.

The exo propanone II-exo is ordinarily isolated from the reactionmixture by aqueous extraction. For this purpose, the reaction mixture towhich water has been added is first washed at a pH of from 2 to 6,preferably from 2 to 6, e.g. 3, for purification with a solvent oflimited or zero miscibility with water. Suitable solvents of limited orzero miscibility with water include C₅-C₆ aliphatic compounds such asn-pentane or n-hexane, C₅-C₆ alicyclic compounds such as cyclohexane,aromatic compounds such as benzene, toluene or xylenes, aliphatic C₄-C₈ethers such as dimethyl ether, tert-butyl methyl ether or diisopropylether or mixtures thereof. Aliphatic C₄-C₈ ethers such as diisopropylether are preferably used.

After the washing, the aqueous phase is adjusted to a pH of, ordinarily,from 7.5 to 12, preferably from 9 to 11, e.g. 10, with a suitable base,preferably in the form of the aqueous solution thereof, and extracted,where appropriate several times, with one of the abovementionedsolvents. Suitable bases include alkali metal or alkaline earth metalhydroxides or alkali metal carbonates. Alkali metal hydroxides or theiraqueous solutions are preferably used, in particular potassium hydroxideor potassium hydroxide solution, or sodium hydroxide or sodium hydroxidesolution. Removal of the solvent from the alkaline extract(s), whichtakes place for example by distillation, preferably under reducedpressure, results in a propanone II which is at least 96% composed ofthe iso isomer II-exo. The propanone II thus has an exci/endo ratio ofat least 24:1. It has not to date been possible to produce a propanoneII with such a high proportion of exo isomer, and it is thus novel andthe present invention likewise relates thereto.

The proportion of the exo isomer II-exo in the propanone II dependsvirtually exclusively on the degree of purity of the exo ethanoneIII-exo employed. Thus, use of an ethanone III with an exo proportion of100% results in a propanone II with an exo proportion of about 100%.

In the reaction according to the invention of the exo ethanone III-exoto give the propanone II, the latter is obtained not only in the form ofexo isomer III-exo, without isomerization being observed, but also inthe considerably larger yield compared with the conventional procedure

The term exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino -1-propanone(II-exo) means here and hereinafter a propanone II which is from 96 to100% composed of the exo propanone II-exo.

The exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone(II-exo) produced according to the invention is subsequently reactedwith a phenylmagnesium compound in a Grignard reaction to produce thebiperiden. Preferred phenylmagnesium compounds are diphenylmagnesium andparticularly preferably phenylmagnesium compound of the general formula

where R′ is C₁-C₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl orn-butyl, C₄-C₆-cycloalkyl, such as cyclohexyl,C₄-C₆-cycloalkyl-C₁-C₄-alkyl, such as 2-cyclohexylethyl,phenyl-C₁-C₄-alkyl, such as benzyl, 2-phenylethyl or 3-phenylpropyl,substituted phenyl-C₁-C₄-alkyl, such as 3,4-(methylenedioxy)benzyl,heteroaryl, such as 8-quinolyl, heteroaryl-C₁-C₄-alkyl, such asfurfuryl, 2-thienylmethyl or 2-(2-thienyl)ethyl, or benzhydryl. Thereaction is normally carried out in a solvent suitable for Grignardreactions. The phenylmagnesium compound of the formula depicted above isreferred to hereinafter as phenylmagnesium alkoxide.

Suitable solvents are aromatic compounds such as benzene, toluene, orxylenes, acyclic or cyclic ethers having 4 to 6 carbon atoms, mixturesthereof or mixtures of them with aliphatic or alicyclic hydrocarbonssuch as n-hexane or cyclohexane. Examples of suitable alicyclic ethersare diethyl ether and tert-butyl methyl ether, and examples of suitablecyclic ethers are tetrahydrofuran and dioxane. Diethyl ether,tetrahydrofuran or dioxane or mixtures thereof are preferably used. Thesolvents are usually employed anhydrous, as normal for Grignardreactions.

The phenylmagnesium alkoxide is prepared in a generally known manner,eg. by reacting diphenylmagnesium with an alcohol of the general formulaR′OH in which R′ is as defined above. Diphenyl-magnesium and the alcoholare for this purpose reacted in a molar ratio in the range from 1:0.9 to1:1.5, preferably in the range from 1:1 to 1:1.2 and particularlypreferably approximately equimolar. Diphenylmagnesium, which is usuallygenerated in situ as described hereinafter, is ordinarily introducedinto one of the abovementioned solvents suitable for Grignard reactions,and the alcohol is normally added in portions over a period of from 5minutes up to about one hour at a temperature of from 0 to 80° C.,preferably from 0 to 50° C. and particularly preferably from 0 to 40° C.After the addition is complete, the mixture can be left, or preferablystirred, in the same temperature range for 15 minutes to 2 hours,preferably 15 minutes to one hour, until the reaction is complete.

The diphenylmagnesium employed in the method of the invention isproduced in a manner known per se. For example, dioxane can be added toa phenylmagnesium halide, e.g. phenylmagnesium chloride, in a suitablesolvent, thus shifting the Schlenk equilibrium to result indiphenylmagnesium and the corresponding magnesium halide-dioxanecomplex. The latter usually precipitates, but is preferably not removedfrom the solution. Suitable solvents are generally acyclic and cyclicethers preferably having 4 to 6 C atoms or mixtures thereof withaliphatic, alicyclic or aromatic hydrocarbons. Examples of suitableacyclic ethers are diethyl ether and tert-butyl methyl ether, and asuitable cyclic ether is tetrahydrofuran. The suitable aliphatic andalicyclic hydrocarbons include in particular n-hexane and cyclohexane,and examples of suitable aromatic hydrocarbons are benzene, toluene andxylenes.

Dioxane is ordinarily employed at least equimolar in relation to thephenylmagnesium halide. If diphenylmagnesium is to be used asphenylmagnesium compound, then dioxane is preferably employed in excess,for example in an excess of from 50 to 500 mol %, in particular from 100to 300 mol % and specifically of from 100 to 200 mol %. Ifdiphenylmagnesium is first to be converted into the phenylmagnesiumalkoxide, preferably dioxane and the phenylmagnesium halide are erployedin a molar ratio in the range from 1:1 to 1.5:1, in particular 1:1 to1.2:1 and particularly preferably approximately equimolar.

The dioxane is added to the s;olution of the phenylmagnesium halideusually at a temperature in the range from −20 to 60° C., preferably inthe range from −10 to 40° C.

The mixture obtained after addition of the dioxane is normally left forfrom 15 minutes to 2 hours, preferably 20 minutes to one hour, in thetemperature range mentioned for the addition of the dioxane, before itis employed in the method of the invention.

Both the preparation of diphenylmagnesium, the reaction to give thephenylmagnesium alkoxide and the Grignard reaction with the exopropanone II-exo are suitably carried out under an inert gas atmosphere.Examples of suitable inert gases are nitrogen and the noble gases suchas argon, and mixtures thereof.

In the Grignard reaction of the exo propanone II-exo with thephenyl-magnesium compound, ordinarily the phenylmagnesium compound andthe exo propanol II-exo are employed in a molar ratio in the range from0.8:1 to 3:1, preferably in the range from 0.8:1 to 2:1 and inparticular in the range from 0.8:1 to 1.5:1. Where diphenylmagnesium orthe phenylmagnesium alkoxide is used, the phenylmagnesium compound andthe exo propanone II-exo are particularly preferably employed in a molarratio in the range from 1:1 to 1.3:1.

Ordinarily, the exo propanone II-exo is added to the phenylmagnesiumcompound in the form of a solution in one of the abovementioned organicsolvents suitable for Grignard reactions at a temperature in the rangefrom −20° C. to the boiling point, preferably in the range from −10° C.to 90° C. and particularly preferably in the range from 0° C. to 70° C.The phenylmagnesium compound is moreover ordinarily employed in aconcentration in the range from 0.1 to 10 mol/l, preferably in the rangefrom 0.1 to 3 mol/l and particularly preferably in the range from 0.2 to2 mol/l.

The exo propanone II-exo can be added in one portion or, preferably,over a period of from a few minutes up to several hours, e.g. 5 minutesto 5 hours. The exo propanone II-exo is added either in the form of asolution in one of the abovementioned inert solvents suitable forGrignard reactions or, preferably, in pure form. When added as solution,the concentration of the exo propanbne II-exo is ordinarily from 0.1 to20 mol/l, preferably 1 to 15 mol/l. To complete the reaction, thereaction mixture is normally left at a temperature in the range from−20° C. to the boiling point of the reaction mixture, preferably in therange from −10° C. to 90° C. and particularly preferably in the rangefrom 10° C. to 80° C. for from 15 minutes to 5 hours, specifically 30minutes to 2 hours, during which it is preferably stirred to improvemixing. Workup is, as usual for Grignard reactions, by aqueousextraction, e.g. by quenching the reaction mixture with water, anaqueous ammonium chloride solution or an acidic aqueous solution, withthe pH of the resulting mixture in the latteir case subsequently beingmade alkaline, extracting the quenched mixture, where appropriate afterremoval of an organic phase, with a water-immiscible solvent suitablefor dissolving the product, and removing the solvent from the extract orfrom the extract combined with the organic phase. Examples of suitablesolvents are aromatic compounds such as benzene or toluene, theabovementioned acyclic ethers, esters such as ethyl acetate orchlorine-containing aliphatic compounds such as dichloromethane ortrichloromethane.

The crude product obtained from the reaction according to the inventionof the exo propanone II-exo with diphenylmagnesium or with aphenylmagnesium alkoxide consists essentially of the two diastereomericpairs of exo enantiomers Ia and Ib of1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I),with the pair of enantiomers Ia (biperiden) forming by far the majorquantity. The ratio of biperiden (Ia) to the pair of enantiomers Ibdetermined by gas chromatography is frequently about 4:1.

The biperiden (Ia) is isolated from the mixture of diastereomers bydissolving the latter with heating, preferably at a temperature of from40 to 80° C., in particular from 50 to 70° C., in a mixture of water anda polar, water-miscible organic solvent. Suitable solvents areC₁-C₃-alkanols, i.e. methanol, ethanol, n-propanol and isopropanol.Aqueous isopropanol is preferably used, particularly preferably 70 to95% isopropanol and especially 90% isopropanol. The percentage datagiven here and hereinafter in relation to the isopropanol content arebased on the volume of the isopropanol relative to the total volume ofthe water-containing solvent. HCl is added to this solution, for examplein the form of a solution of hydrogen chloride in an organic solvent,preferably in one of the C₁-C₃-alkanols mentioned, with preference inisopropanol, or in the form of hydrochloric acid. HCl is employed atleast equimolar in relation to the mixture of the diastereomeic aminoalcohols, preferably in an excess of from 5 to 50 mol % and particularlypreferably from 5 to 20 mol %. The addition preferably takes place atelevated temperature, e.g. at 40 to 80° C. and in particular at 50 to70° C. To complete the reaction after addition is complete, the reactionmixture is left at a temperature of from 50° C. up to the boiling pointof the reaction mixture for 0.5 to 3 hours, preferably while stirring.In a preferred embodiment, the reaction mixture is stirred at 55 to 65°C. for the first two thirds of the time and then stirred at the refluxtemperature for one third of the time. The reaction mixture is thencooled to a temperature in the range from 0 to 30° C., where appropriatestirred in this temperature range for up to several hours, e.g. up to 10hours, preferably up to 5 hours, and then the hydrochloride which hasformed is removed from the solution in a conventional way.

For further purification of the hydrochloride, it is generally taken upwet or dry in water and a sufficient amount of one or more polar dialkylethers of limited or zero miscibility with water and having 4 to 8 Catoms, such as diethyl ether, tert-butyl methyl ether and especiallydiisopropyl ether, and a suitable base is added to the mixture. Suitableamounts of organic solvents are, for example, from 4 to 10 ml of solventper gram of dry hydrochloride. Water and organic solvent are preferablyemployed in a ratio in the range from 1:2 to 1:5 by volume.

Suitable bases are alkali metal and alkaline earth metal hydroxides, andalkali metal carbonates; sodium or potassium hydroxide or their aqueoussolutions are particularly preferably used, sodium hydroxide or sodiumhydroxide solution are especially used. However, it is also possible touse water-soluble organic bases, for example amines having aliphaticsubstituents and 2 to 8 C atoms. The base is employed at leastequimolar, preferably in excess, in particular in an excess of from 5 to15 mol % based on the hydrochloride.

The reaction with the base preferably takes place at elevatedtemperature. For this purpose, before, during or, preferably, afteraddition of the base the mixture is heated to a temperature in the rangeabove 25° C. up to the boiling point of the reaction mixture, preferablyin the range from 30 to 70° C., and when diisopropyl ether is used asdialkyl ether preferably in the range from 40 to 65° C., in particularfrom 55 to 60° C. This generally results in two clear phases which areseparated at elevated temperature, in the case where diisopropyl etheris used as dialkyl ether in the abovementioned temperature range. Theorganic phase is washed with water at elevated temperature, in the casewhere diisopropyl ether is used as dialkyl ether in the abovementionedtemperature range, and then concentrated preferably under atmosphericpressure by removing the solvent until the weight/volume ratio of theproduct to the solvent is in the range from 1:2 to 1:6, preferably from1:3 to 1:4.5. When the mixture is cooled to room temperature or below,but preferably not below −10° C., pure biperiden (Ia) crystallizes outand is isolated by conventional methods for isolating solids, e.g.filtering off the solid or decanting off the mother liquor.

It was possible by the use according to the invention of a propanone IIhaving a proportion of at least 96% of exo to increase the yield ofbiperiden (Ia) considerably, especially in combination with the workupdescribed above

Biperiden (Ia) can then be converted with a pharmacologically acceptableacid in a conventional manner into its acid addition salt. Examples ofsuitable acids are hydrohalic acids, in particular hydrogen chloride orhydrochloric acid, and organic mono- or dicarboxylic acids such asacetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, adipic acid or benzoic acid, also phosphoric acid andsulfuric acid, and the acids mentioned in “Fortschritte derArzneimittelforschung, volume 10, pages 224 et seq., Birkhäuser Verlag,Basle, Stuttgart, 966”. Biperiden (Ia) is normally marketed ashydrochloride.

The exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) used toprepare theexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone II-exo isobtained by a Diels-Alder cycloaddition reaction of cyclopentadiene andmethyl vinyl ketone. A particularly preferred method for preparing III,which affords a product with a high content of III-exo, is described inthe German patent application 10124450.9, the disclosure of which isincorporated herein by reference. The cycloaddition of cyclopentadieneand methyl vinyl ketone can be carried out in a solvent conventional forsuch reactions, such as diethyl ether, benzene, toluene or xylene orelse without solvent. It is preferred to use no solvent. Cyclopentadieneand methyl vinyl ketone are normally employed in a molar ratio in therange from 3.0:1 to 0.5:1. They are preferably reacted equimolar or withcyclopentadiene in excess, with the excess preferably being 50 to 150mol %.

The reaction is usually carried out at a temperature in the range from 0to 60° C., preferably in the range from 10 to 40° C.

Low-boiling constituents, usually unreacted precursors, are usuallyremoved following the cycloaddition by distillation under reducedpressure, preferably under 1 to 150 mbar. The remaining mixture, whichconsists of about 20% exo- and about 80%endo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone, is reacted with an alkalimetal C₁-C₄-alcoholate. The amount of alkali metal alcoholate is usuallyfrom 0.1 to 5% by weight, preferably from 0.2 to 2% by weight, based onthe total weight of the mixture. Sodium methanolate is preferably used.The temperature necessary for isomerization of the ethanone III isusually in the range from 50 to 110° C., preferably in the range from 60to 100° C. For this purpose, the mixture is often heated under reducedpressure to reflux, preferably under a pressure of from 1 to 100 mbarand in particular under a pressure of from 5 to 50 mbar. Theseconditions are usually applied for from 10 minutes to hours, inparticular 20 minutes to 3 hours and specifically 0.5 hours to 2 hours,and then fractional distillation of the resulting mixture is started,preferably distilling out the exo isomer of III. It is assumed thatremoval of the exo isomer from the equilibrium promotes isomerization ofthe endo ethanone to the exo form. The fractional distillation normallytakes place through a column under reduced pressure, preferably in therange from 1 to 100 mbar, in particular from 1 to 50 and specificallyfrom 1 to 20 mbar. The distillation temperature (distillate temperature)is preferably adjusted to from 50 to 100° C. and specifically to 50 to80° C. In this way, exo-1-(bicyclo[2.2.1]-hept-5-en-2-yl)ethanone(III-exo) is obtained in a purity which is at least 96%.

Redistillation of the distillate results in purities of up to 100%. Exoethanone III-exo with a purity of at least 96% is used in the method ofthe invention.

The following examples serve to illustrate the invention but are not tobe understood as restrictive.

EXAMPLE 1. Preparation of the Starting Material

1.1 exo-1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo)

198.3 g of cyclopentadiene were rapidly added to 210.3 g of methyl vinylketone. After the addition was complete, the reaction solution wasstirred at room temperature for one hour and then unreacted precursorwas removed by distillation at a temperature of 58° C. and a pressure of20 mbar. The residue from evaporation, mainly consisting of a mixture ofthe exo and the endo form of 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone(III) in the ratio of 1:4, was heated to reflux with 5 g of sodiummethanolate under a pressure of from 10 to 20 mbar for one hour. Thereaction mixture was then distilled through a column at a temperature of75° C. and a pressure of 20 mbar. This resulted in 298.3 g (73% oftheory) of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) in theform of a pale yellowish oil.

1.2 exo-1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone(II-exo)

1.2.1 Preparation of the trimethylsilyl enol ether of the exo ethanoneIII-exoexo-({1-[bicyclo[2.2.1]hept-5-en-2-yl]-vinyl}oxy)(trimethyl)silane (IVwith R=methyl)

68.1 g of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III -exo),obtained as in example 1.1, were added dropwise over the course of 30minutes to 250 ml of a 2M lithium diisopropylamide solution intetrahydrofuran/ethylbenzene/n-heptane at −78° C. The mixture wasstirred at −78° C. for a further hour. Then, at −78° C., 67.9 g oftrimethylsilyl chloride were rapidly added dropwise. The cooling bathwas removed and the solution was thawed to room temperature over thecourse of about 1.5 hours. the precipitate which had formed was filteredoff with suction and washed with 100 ml of n-hexane. The combinedfiltrates were extracted with 250 ml of cold saturated aqueous sodiumbicarbonate solution, and the phases were separated. The aqueous phasewas then extracted three times with 100 ml of n-hexane each time. Thethree organic extracts were added to the combined filtrates, and theorganic phase obtained in this way was dried over sodium sulfate. Thesolvent was removed and the resulting crude product was purified bydistillation at 95° C./20 mbar. The distillate obtained was 83.4 g ofexo-({1-[bicyclo[2.2.1]hept-5-en-2-yl]vinyl}oxy)-(trimethyl)silane (IV,R=methyl) in the form of a colorless oil; which is 80% of theory.

1.2.2 Preparation of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II-exo)

83.4 g ofexo-({1-[bicyclo[2.2.1]hept-5-en-2-yl]vinyl}oxy)-(trimethyl)silane (IV,R=methyl), obtained as in example 1.2.1, were introduced into 50 ml ofN,N-dimethylformamide at −25° C. Subsequently, 73.5 g ofN-methylenepiperidinium chloride were added, and the cooling bath wasremoved. The reaction mixture was stirred for 30 minutes and then addedto 250 ml of cold water. The pH was adjusted to about 3 with dilutehydrochloric acid, and the solution was extracted three times with 75 mlof diisopropyl ether each time. The organic extracts were discarded. Theaqueous phase was then adjusted to a pH of 10 with 50% concentratedsodium hydroxide solution and extracted three times with 75 ml ofdiisopropyl ether each time. The combined organic extracts were driedover sodium sulfate, and the solvent was removed in vacuo. This resultedin 91.5 g ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II-exo)in the form of a colorless oil; which is 98% of theory.

2. Preparation of Biperiden (Ia)

103.1 g of dioxane were added dropwise at 0° C. to 640 g of a 25%strength solution of phenylmagnesium chloride in tetrahydrofuran, duringwhich a white precipitate formed. After stirring while cooling in an icebath for 30 minutes, 71.5 g of 2-phenylethanol were added to themixture. After stirring while cooling in an ice bath for a further 30minutes, 91.5 g ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II-exo),obtained as in example 1.2.2, were added while cooling in an ice bath.After the addition was complete, the ice bath was removed and thereaction mixture was stirred without cooling for a further hour. Themixture was then added slowly to 750 ml of ice-cold water. This wasfollowed by extraction three times with 100 ml of toluene each time. Thecombined extracts were dried over sodium sulfate and evaporated in arotary evaporator. The residue from evaporation—155.5 g of a mixturewhich consisted essentially of forms Ia and Ib of1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I) inthe ratio (GC) 4:1—was dissolved in 750 ml of isopropanol at the refluxtemperature, 200 ml of water were added to the solution, and the 25mixture was cooled to 60° C. At this temperature, 78 ml of 5Mhydrochloric acid were added. Addition of acid was followed by stirringat 60° C. for one hour and then at the reflux temperature for half anhour. After cooling to room temperature, the crystals which hadseparated out were removed, washed with 150 ml of isopropanol and driedin vacuo at 70° C. The hydrochloride (66.5 g) obtained in this way wasstirred in 375 ml of diisopropyl ether and 100 ml of water while 78 mlof 5M sodium hydroxide solution were added. The mixture was stirred atthe reflux temperature for minutes, the aqueous phase was separated offhot, and 150 ml of solvent were removed from the organic phase bydistillation under atmospheric pressure. The residue from distillationwas allowed to cool to room temperature while stirring. After coolingfor a further hour in an ice bath, the crystals which had separated outwere removed, washed with 20 ml of diisopropyl ether and dried in vacuoat 40° C. 53.5 g of biperiden (Ia) were obtained as colorless crystalsof melting point 112 to 114° C. (Ullmanns Enzyklopädie der techn.Chemie, 4th edition, volume 21, Verlag Chemie, 1982, page 627: 112-114°C.); which is 44% of theory.

3. Preparation of Biperiden Hydrochloride

93.4 g of biperiden (Ia) were dissolved in 1 000 ml of isopropanol byheating to the reflux temperature. The solution was filtered hot, andthe filter was washed with 100 ml of isopropanol. 65 ml of 5Mhydrochloric acid were added to the combined filtrates at 75° C. Themixture was then heated to reflux for 15 minutes. After cooling to roomtemperature and stirring at this temperature for one hour, theprecipitated solid was filtered off with suction, washed twice with 50ml of isopropanol each time and dried in vacuo at 70° C. 103.2 g ofbiperiden hydrochloride were obtained in the form of colorless crystalsof melting point 278 to 280° C. (Ullmanns Enzyklopädie der techn.Chemie, 4th edition, volume 21, Verlag Chemie, 1982, page 627: 278-280°C.); which is 98.9% of theory.

1. A method for producing biperiden by reactingexo-l-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-l-propanone with aphenylmagnesium compound, characterized in that the production of theexo-1-(bicyclo(2.2.1]hept-5-en-2-yl)-3-piperidino-l-propanone comprisesthe following steps: a) conversion ofexo-l-(bicyclo[2.2.1]hept-5-en-2-yl)-ethanone into an exo silyl enolether IV

in which R₃ may be identical or different and is alkyl or cycloalkyl,and b) reaction of the exo silyl enol ether with anN-methylenepiperidinium compound.
 2. The method of claim 1,characterized in that in step a) the exo ethanone is converted with ametal amide as base into the exo metal enolate V

and the latter is then converted with an organosilicon compound of theformula R₃Si-X, in which R₃ has the aforementioned meaning, and X is ahalogen atom, into the exo silyl enol ether IV.
 3. The method of claim2, characterized in that an alkali metal amide is used as the metalamide.
 4. The method of claim 3, characterized in that a lithium amideis used as the alkali metal amide.
 5. The method of claim 4,characterized in that lithium diisopropylamide is used as the lithiumamide.
 6. The method of claim 2, characterized in that the exo ethanoneand the metal amide are employed in a molar ratio of exo ethanone tometal amide in the range from 1:1 to 1:1.5.
 7. The method of claim 1,characterized in that exo-l-(bicyclo [2.2. 1]hept-5-en2-yl)ethanone isconverted into the exo trimethylsilyl enol ether with R ═ methyl.
 8. Themethod of claim 7, characterized in that trimethylsilyl chloride is usedin step a).
 9. The method of claim 1, characterized in that step a) iscarned out at a temperature in the range from -100 to 0° C.
 10. Themethod of claim 1, characterized in that methylenepiperidinium chlorideis used in step b).
 11. The method of claim 10, characterized in thatthe N-methylenepiperidinium compound is reacted with the exo silyl enolether in step b) in a molar ratio in the range from 1:1 to 2:1.
 12. Themethod of claim 1, characterized in that step b) is carried out at atemperature in the range from -60 to 10° C.
 13. The method of claim 1,characterized in that the reaction mixture resulting in step b) isconverted into an aqueous solution, and the latter is washed at a pH notexceeding 6 with a solvent of limited or zero miscibility with water,the resulting raffinate is extracted at a pH of at least 7.5 with asolvent of limited or zero miscibility with water, and the solvent isremoved from the extract, resulting inexo-l-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-l-propanone.
 14. Themethod of claim 1, characterized in that the phenylmagnesium, compoundused is diphenylmagnesium or a phenylmagnesium. compound of the generalformula

where R′ is C₁-C₄-alkyl, C₄-C₆-cycloalkyl,C₄-C₆-cycloalkyl-C₁-C₄-alkyl,phenyl-C₁-C₄alkyl, substituted phenyl-C₁-C₄-alkyl, heteroaryl,heteroaryl-C₁C₄-alkyl or benzhydryl.
 15. The method of claim 1,characterized in that to isolate biperiden from the reaction of theexo-l-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanoe with thephenylmagnesium compound, the mixture of diastereomeric1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanols formedthereby is converted in aqueous isopropanol into the hydrochloride whichis isolated, the hydrochloride is reacted with a base in water anddiisopropyl ether, the aqueous phase is removed at elevated temperature,and part of the diisopropyl ether is removed from the organic phase and,after cooling, biperiden is isolated by removing the solid from themother liquor.
 16. The method as claimed in any of claim 1 or 15,wherein an exo-(1-[bicyclo(2.2.1]hept-5-en-2-yl]vinyl)oxy)silane offormula IV is produced as an intermediate compound, wherein

R₃ is identical or different and is alkyl or cycloalkyl.
 17. The methodof claims 1, 15 or 16, wherein said method yields1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with anexo/endo ratio of at least 24:1.